Objective: To systematically review genotype-phenotype correlations for the four known genes causing EA.

Background: EA is a group of heterogeneous disorders characterized by recurrent attacks of gait and limb ataxia. EA is usually inherited in an autosomal dominant manner and commonly associated with CACNA1A, SLC1A3, KCNA1,andPDHA1mutations. There can be other paroxysmal neurological symptoms in addition to the ataxia. Mutations in the same genes can also lead to non-paroxysmal neurological signs and symptoms. There may be quite broad overlap of triggers across genes. There is a knowledge gap in understanding the phenotype-genotype correlation in EA. Previous meta-analysis done as a part of MDSGene project for other disorders revealed several discrepancies when compared to expert knowledge.

Method: A systematic review of the published literature was conducted. PubMed was searched using standardized search terms for studies reporting clinical data on individual patients with any movement disorder with or without episodic symptoms and a mutation in any one of the CACNA1A, SLC1A3, KCNA1, or PDHA1 genes. We followed MDSGene’s standardized data extraction protocol. Pathogenicity of each reported mutation was assessed using standard criteria.

Results: The search yielded 766 papers. Following title/abstract screening,157 papers (CACNA1A-116, SLC1A3-5, KCNA1-23, PDHA1-13) were deemed eligible for full-text review. These papers contained information on 468 individuals in the four EA genes (CACNA1A-313, SLC1A3-8, KCNA1-106, PDHA1-41). The frequency of mutations in reported individuals and pathogenicity scores for each mutation from the available data will be presented. Clinical and demographic features will be extracted for each mutation carrier individually and compared across the genes. All the extracted data will be presented and available in an online database (www.mdsgene.org), which provides descriptive summary statistics on phenotypic and genetic data.

Conclusion: This systematic review represents a comprehensive overview of the currently publically available phenotypic and genotypic data on EA genes. It also assesses the pathogenicity of reported potentially causative mutations in correlation with associated phenotype. This review enables stratified analyses in selected patient subgroups expanding the understanding of EA phenotypes and molecular basis, which is imperative in the era of trials involving gene-specific therapies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genotype-phenotype-correlations-of-episodic-ataxia-ea-mdsgene-systematic-review/